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CA-3256250-A1 - PD-L1 VARIANT IMMUNOMODULATORY PROTEINS AND USES THEREOF

CA3256250A1CA 3256250 A1CA3256250 A1CA 3256250A1CA-3256250-A1

Abstract

Provided herein are immunomodulatory proteins comprising variant PD-L1 and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.

Inventors

  • Ryan Swanson
  • Michael Kornacker
  • Mark F. Maurer
  • Dan ARDOUREL
  • Daniel William DEMONTE
  • Joseph L. Kuijper

Assignees

  • ALPINE IMMUNE SCIENCES, INC.

Dates

Publication Date
20260302
Application Date
20180313
Priority Date
20170316

Claims (1)

  1. <pat:ClaimStatement>WHAT IS CLAIMED:</pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1</pat:ClaimNumber> <pat:ClaimText>1. A variant PD-L1 polypeptide, comprising an IgV domain or a specific binding fragment thereof, an IgC domain or a specific binding fragment thereof, or both, wherein the variant PD-L1 polypeptide comprises one or more amino acid modifications at one or more positions in an unmodified PD-L1 or a specific binding fragment thereof corresponding to position(s) selected from 45, 43, 6, 10, 11, 14, 15, 16, 17, 18, 19, 20, 22, 23, 26, 27, 28, 33, 35, 36, 40, 41, 44, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 64, 65, 68, 71, 72, 73, 74, 75, 78, 79, 83, 85, 89, 90, 93, 97, 98, 99, 101, 102, 103, 104, 106, 110, 111, 112, 113, 117, 119, 120, 121, 124, 129, 130, 131, 134, 137, 138, 144, 148, 149, 150, 155, 158, 160, 163, 165, 167, 170, 171, 173, 175, 176, 177, 179, 180, 183, 185, 188, 189, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 206, 207, 213, or 221, with reference to the numbering of SEQ ID NO:30. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2</pat:ClaimNumber> <pat:ClaimText>2. The variant PD-L1 polypeptide of claim 1, wherein the unmodified PD-L1 comprises (i) the sequence of amino acids set forth in SEQ ID NO:30, (ii) a sequence of amino acids that has at least 95% sequence identity to SEQ ID NO:30; or (iii) a portion thereof comprising an IgV domain or IgC domain or specific binding fragments thereof or both. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3</pat:ClaimNumber> <pat:ClaimText>3. The variant PD-L1 polypeptide of claim 1 or claim 2, wherein the variant PD-L1 comprises up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid modifications, optionally amino acid substitutions, insertions and/or deletions. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4</pat:ClaimNumber> <pat:ClaimText>4. The variant PD-L1 polypeptide of any of claims 1-3, wherein the variant PD-L1 polypeptide comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:30 or 1728 or a specific binding fragment thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5</pat:ClaimNumber> <pat:ClaimText>5. The variant PD-L1 polypeptide of any of claims 1-4, wherein the one or more amino acid modifications are selected from P6S, Y10F, V11A, V11E, Y14S, G15A, S16G, N17D, M18I, M18T, M18V, T19A, T19I, I20L, C22R, K23E, K23N, K23R, E26A, E27D, E27G, K28E, K28I, K28R, K28N, A33D, L35P, I36S, I36T, E40G, M41K, M41V, D43G, D43V, K44E, N45D, N45I, N45T, I47T, I46V, F49S, V50A, H51N, H51R, H51Y, G52R, G52V, E53G, E53V, E54G, D55G, D55N, D55S, D55V, L56Q, K57E, K57R, V58A, V58D,H60R, R64S, Q65L, R68L, K71E, D72G, Q73R, L74P, S75P, N78I, N78S, A79T, I83T, D85E, Q89R, D90G, V93E, M97I, M97K, M97L, I98L, I98T, I98V, S99G, G101D, G101G-ins (G101GG), G102D, A103V, D104G, K106E, K106R, V110M, K111E, K111T, V112A, N113Y, N117S, I119T, N120S, Q121L, L124S, V129A, V129D, T130A, S131F, E134G, C137R, Q138R, K144E, K144Q, I148V, W149R, T150A, Q155H, S158G, K160M, T163I, K163N, N165Y, K167R, K167T, E170G, K171R, F173I, F173L, K173Y, V175A, T176N, S177C, L179P, R180S, T183A, T183I, T185A, I188V, F189L, F189S, T192S, F193S, R194G, R194W, R195G, R195S, R195T, L196S, D197G, P198S, P198T, E199G, E200K, E200N, N201D, N201Y, H202Q, T203A, A204T, L206F, V207A, L213P, T221L or a conservative amino acid substitution thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6</pat:ClaimNumber> <pat:ClaimText>6. The variant PD-L1 polypeptide of any of claims 1-5, wherein the one or more amino acid modifications are selected from among K28N/M41V/N45T/H51N/K57E I20L/I36T/N45D/I47T, I20L/M41K/K44E, P6S/N45T/N78I/I83T, N78I, M41K/N78I, N45T/N78I, I20L/N45T, N45T, M41K, I20L/I36T/N45D, N17D/N47T/V50A/D72G, I20L/F49S, N45T/V50A, I20L/N45T/N78I, I20L/N45T/V50A, M41V/N45T, M41K/N45T, A33D/S75P/D85E, M18I/M41K/D43G/H51R/N78I, V11E/I20L/I36T/N45D/H60R/S75P, A33D/V50A, S16G/A33D/K71E/S75P, E27G/N45T/M97I, E27G/N45T/K57R, A33D/E53V, D43G/N45D/V58A, E40G/D43V/N45T/V50A, Y14S/K28E/N45T, A33D/N78S, A33D/N78I, A33D/N45T, A33D/N45T/N78I, E27G/N45T/V50A, N45T/V50A/N78S, I20L/N45T/V110M, I20L/I36T/N45T/V50A, N45T/L74P/S75P, N45T/S75P, S75P/K106R, S75P, A33D/S75P, A33D/S75P/D104G, A33D/S75P, I20L/E27G/N45T/V50A, I20L/E27G/D43G/N45D/V58A/N78I, I20L/D43G/N45D/V58A/N78I, I20L/A33D/D43G/N45D/V58A/N78I, I20L/D43G/N45D/N78I, E27G/N45T/V50A/N78I, N45T/V50A/N78I, V11A/I20L/E27G/D43G/N45D/H51Y/S99G, I20L/E27G/D43G/N45T/V50A, I20L/K28E/D43G/N45D/V58A/Q89R, I20L/I36T/N45D, I20L/K28E/D43G/N45D/E53G/V58A/N78I, A33D/D43G/N45D/V58A/S75P, K23R/D43G/N45D, I20L/D43G/N45D/V58A/N78I/D90G/G101D, D43G/N45D/L56Q/V58A/ G101G-ins (G101GG), I20L/K23E/D43G/N45D/V58A/N78I, I20L/K23E/D43G/N45D/V50A/N78I, T19I/E27G/N45I/V50A/N78I/M97K, I20L/M41K/D43G/N45D, K23R/N45T/N78I, I20L/K28E/D43G/N45D/V58A/Q89R/G101G- ins (G101GG), K57R/S99G, K57R/S99G/F189L, M18V/M97L/F193S/R195G/E200K/H202Q, I36S/M41K/M97L/K144Q/R195G/E200K/H202Q/L206F, C22R/Q65L/L124S/K144Q/R195G/E200N/H202Q/T221L, M18V/I98L/L124S/P198T/L206F, S99G/N117S/I148V/K171R/R180S, I36T/M97L/A103V/Q155H, K28I/S99G, R195S, A79T/S99G/T185A/R195G/E200K/H202Q/L206F, K57R/S99G/L124S/K144Q, K57R/S99G/R195G, D55V/M97L/S99G, E27G/I36T/D55N/M97L/K111E, E54G/M97L/S99G, G15A/I36T/M97L/K111E/H202Q, G15A/I36T/V129D, G15A/I36T/V129D/R195G, G15A/V129D, I36S/M97L, I36T/D55N/M97L/K111E/A204T, I36T/D55N/M97L/K111E/V129A/F173L, I36T/D55S/M97L/K111E/I148V/R180S, I36T/G52R/M97L/V112A/K144E/V175A/P198T, I36T/I46V/D55G/M97L/K106E/K144E/T185A/R195G, I36T/I83T/M97L/K144E/P198T, I36T/M97L/K111E, I36T/M97L/K144E/P198T, I36T/M97L/Q155H/F193S/N201Y, I36T/M97L/V129D, L35P/I36S/M97L/K111E, M18I/I36T/E53G/M97L/K144E/E199G/V207A, M18T/I36T/D55N/M97L/K111E, M18V/M97L/T176N/R195G, M97L/S99G, N17D/M97L/S99G, S99G/T185A/R195G/P198T, V129D/H202Q, V129D/P198T, V129D/T150A, V93E/V129D, Y10F/M18V/S99G/Q138R/T203A, N45D, K160M/R195G, N45D/K144E, N45D/P198S, N45D/P198T, N45D/R195G, N45D/R195S, N45D/S131F, N45D/V58D, V129D/R195S, I98T/F173Y/L196S, N45D/E134G/L213P, N45D/F173I/S177C, N45D/I148V/R195G, N45D/K111T/R195G, N45D/N113Y/R195S, N45D/N165Y/E170G, N45D/Q89R/I98V, N45D/S131F/P198S, N45D/S75P/P198S, N45D/V50A/R195T, E27D/N45D/T183A/I188V, F173Y/T183I/L196S/T203A, K23N/N45D/S75P/N120S, N45D/G102D/R194W/R195G, N45D/G52V/Q121L/P198S, N45D/I148V/R195G/N201D, N45D/K111T/T183A/I188V, N45D/Q89R/F189S/P198S, N45D/S99G/C137R/V207A, N45D/T163I/K167R/R195G, N45D/T183A/T192S/R194G, N45D/V50A/I119T/K144E, T19A/N45D/K144E/R195G, V11E/N45D/T130A/P198T, V26A/N45D/T163I/T185A, K23N/N45D/L124S/K167T/R195G, K23N/N45D/Q73R/T163I, K28E/N45D/W149R/S158G/P198T, K28R/N45D/K57E/I98V/R195S, K28R/N45D/V129D/T163N/R195T, M41K/D43G/N45D/R64S/R195G, M41K/D43G/N45D/R64S/S99G, N45D/R68L/F173L/D197G/P198S, N45D/V50A/I148V/R195G/N201D, M41K/D43G/K44E/N45D/R195G/N201D, or N45D/V50A/L124S/K144E/L179P/R195G. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7</pat:ClaimNumber> <pat:ClaimText>7. The variant PD-L1 polypeptide of any of claims 1-6, wherein the one or more amino acid modifications are at one or more positions corresponding to position(s) selected from 20, 27, 33, 36, 43, 45, 50, 58, 75 or 78. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8</pat:ClaimNumber> <pat:ClaimText>8. The variant PD-L1 polypeptide of any of claims 1-7, wherein the one or more amino acid modifications are selected from I20L, E27G, A33D, I36T, D43G, N45D, N45T, V50A, V58A, S75P, N78I, or a conservative amino acid substitution thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9</pat:ClaimNumber> <pat:ClaimText>9. The variant PD-L1 polypeptide of any of claims 1-8, wherein the variant PD-L1 polypeptide comprises amino acid modifications I20L/I36T, I20L/D43G, I20L/N45D, I20L/N45T, I20L/N45T, I20L/V50A, I20L/V58A, I20L/S75P, I20L/N78I, I36T/D43G, I36T/N45D, I36T/N45T, I36T/V50A, I36T/V58A, I36T/S75P, I36T/N78I, D43G/N45D, D43G/N45T, D43G/V50A, D43G/V58A, D43G/S75P, D43G/N78I, N45D/V50A, N45D/V58A, N45D/S75P, N45D/N78I, N45T/V50A, N45T/V58A, N45T/S75P, N45T/N78I, V50A/V58A, V50A/S75P, V50A/N78I, V58A/S75P, V58A/N78I, or S75P/N78I. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10</pat:ClaimNumber> <pat:ClaimText>10. The variant PD-L1 polypeptide of any of claims 1-9, wherein the variant PD-L1 polypeptide comprises amino acid modifications D43G/N45D/V58A. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11</pat:ClaimNumber> <pat:ClaimText>11. The variant PD-L1 polypeptide of any of claims 1-10, wherein the variant PD- L1 polypeptide comprises amino acid modifications D43G/N45D/L56Q/V58A/G101G-ins (G101GG) or I20L/K28E/D43G/N45D/V58A/Q89R/G101G-ins (G101GG). </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12</pat:ClaimNumber> <pat:ClaimText>12. The variant PD-L1 polypeptide of any of claims 1-11, wherein: the variant PD-L1 polypeptide comprises the PD-L1 extracellular domain (ECD); and/or the variant PD-L1 polypeptide comprises the IgV domain or a specific fragment thereof and the IgC domain or a specific fragment thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13</pat:ClaimNumber> <pat:ClaimText>13. The variant PD-L1 polypeptide of any of claims 1-12, comprising the sequence of amino acids set forth in any of SEQ ID NOS: 56-120, 1725, 1729-1818, 1819-1907, 1943- 2008 or a specific binding fragment thereof, or a sequence of amino acids that exhibits at least 95% sequence identity to any of SEQ ID NOS: 56-120, 1725, 1729-1818, 1819-1907, 1943- 2008 or a specific binding fragment thereof and that contains the one or more of the amino acid modifications thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14</pat:ClaimNumber> <pat:ClaimText>14. The variant PD-L1 polypeptide of any of claims 1-19, wherein the variant PD- L1 polypeptide comprises the IgV domain or a specific binding fragment thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15</pat:ClaimNumber> <pat:ClaimText>15. The variant PD-L1 polypeptide of any of claims 1-20, wherein the IgV domain or specific binding fragment thereof is the only PD-L1 portion of the variant PD-L1 polypeptide. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16</pat:ClaimNumber> <pat:ClaimText>16. The variant PD-L1 polypeptide of any of claims 1-15, comprising the sequence of amino acids set forth in any of SEQ ID NOS: 121-185, 244-308, 1726-1727, 1908-1937 or a specific binding fragment thereof, a sequence of amino acids that exhibits at least 95% sequence identity to any of SEQ ID NOS: 121-185, 244-308, 1726-1727, 1908-1937 or a specific binding fragment thereof and that contains the one or more of the amino acid modifications thereof. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17</pat:ClaimNumber> <pat:ClaimText>17. The variant PD-L1 polypeptide of any of claims 1-16, wherein the variant PD- L1 polypeptide specifically binds to the ectodomain of PD-1 with increased affinity compared to the binding of the unmodified PD-L1 to the ectodomain of PD-1. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18</pat:ClaimNumber> <pat:ClaimText>18. The variant PD-L1 polypeptide of any of claims 1-17, wherein the variant PD- L1 polypeptide specifically binds to the ectodomain of PD-1 with increased affinity and specifically binds to the ectodomain of CD80 with decreased affinity compared to the binding of the unmodified PD-L1 to the same ectodomains. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19</pat:ClaimNumber> <pat:ClaimText>19. The variant PD-L1 polypeptide of claim 17 or claim 18, wherein the increased affinity to the ectodomain of PD-1 is increased more than 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold or 60-fold. </pat:ClaimText> </pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20</pat:ClaimNumber> <pat:ClaimText>20. The variant PD-L1 polypeptide of claim 18 or claim 19, wherein the decreased affinity to the ectodomain of CD80 is decreased more than 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold or 60-fold. </pat:ClaimText> </pat:Claim> </pat:Claims>